In the past, various attempts have been made to obtain new and more effective oral anti-diabetic agents. Generally, these efforts have involved synthesis of new organic compounds, particular sulfonyl ureas, and determination of their ability to substantially lower blood sugar levels when administered orally. However, little is known about the effect of organic compounds in preventing or alleviating chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy. U.S. Pat. No. 3,821,383 discloses aldose reductase inhibitors, such as 1,3-dioxo-1H-benz[d,e]-isoquinoline-2(3H)-acetic acid and derivatives thereof, to be useful for the treatment of these conditions. Such aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses such as glucose and galactose to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nervous cord and kidney of various diabetic subjects are prevented or reduced. Accordingly, such compounds are of therapeutic value as aldose reductase inhibitors for controlling certain chronic diabetic complications, including those of an ocular nature, since it is known in the art that the presence of polyols in the lens of the eye leads to cataract formation, with a concomitant loss of lens clarity.
U.S. Pat. No. 4,130,714 discloses certain dextrorotatory spiro-hydantoin compounds which are extremely useful when employed in therapy as aldose reductase inhibitors for the control of chronic complications arising in a diabetic subject. The said compounds are dextrorotatory forms of asymmetric spiro-hydantoins of the formula: ##STR1## and the base salts thereof with pharmacologically acceptable cations, wherein Y is oxygen or sulfur. Typical compounds disclosed in U.S. Pat. No. 4,130,714 include d-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and d-6'-fluoro-spiro[imidazolidine-4,4'-thiochroman]-2,5-dione, respectively. These two particular compounds are both extremely potent as regards their aldose reductase inhibitory activity, in addition to being equally effective in lowering sorbitol levels in the sciatic nerve and lens of diabetic subjects and galactitol levels in the lens of galactosemic subjects to a very significantly high degree.
U.S. Pat. No, 4,193,996 also discloses spiroquinolone hydantoins which are aldose reductase inhibitors useful as therapeutic agents for preventing or alleviating chronic diabetic complications. Said hydantoin compounds are of the formula: ##STR2## and the pharmaceutically acceptable addition salts thereof, wherein n is one or two; R, R.sub.3 and R.sub.4 are each hydrogen; and R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms.
U.S. Pat. No. 4,235,911 disclosed certain tetrahydroquinoline spiro-hydantoin compounds which also are useful when employed in therapy as aldose reductase inhibitors for the control of certain chronic complications arising in a diabetic subject. These compounds are of the formula: ##STR3## and the pharmaceutically acceptable acid addition salts thereof, wherein X is hydrogen and X.sup.1 is hydrogen, lower alkoxy, fluorine, chlorine, bromine or phenyl; X and X.sup.1, when taken separately, are each lower alkoxy, chlorine or phenyl, and when taken together are --OCH.sub.2 (CH.sub.2).sub.n O-- wherein n is zero or one, and R is hydrogen or lower alkyl, with the proviso that R is always other than hydrogen when X.sup.1 is hydrogen. It has now been found that certain novel tetracyclic spiro-hydantoin derivatives are very potent inhibitors of aldose reductase and are useful in treating diabetic complications.